Androgens are produced by testes and adrenal glands and they play a critical role in the development and physiology of normal prostate. The etiology of benign prostate hyperplasia (BPH) and prostatic neoplasia which can progress to adenocarcinoma is androgen-dependent. Treatment of choice for BPH and prostate cancer (PCa) is reduction of androgen action in the prostate. In fact, almost 90% of men between ages 40-90 years develop either BPH or PCa. PCa is the second leading cause of cancer-related death and the most frequently diagnosed malignancy in men. PCa remains incurable in metastatic setting. As the incidence of PCa increases with age, the number of newly diagnosed cases rises continuously due to increased life expectancy of the population.
The conventional initial treatment for PCa is hormone or androgen deprivation therapy (ADT). Experimental ADT was first described already in 1941. ADT via surgical castration or by chemical castration using luteinizing hormone releasing hormone agonists is universally accepted first-line therapy in advanced PCa. See Perlmutter M, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer Rev Urol. 2007; 9(Suppl 1): S3-S8 and references therein.
Maximal androgen blockade is achieved by combining ADT with an anti-androgen treatment. Anti-androgens compete with endogenous androgens, testosterone and dihydrotestosterone, for binding in the ligand-binding pocket of the androgen receptor (AR). AR belongs to the superfamily of nuclear hormone receptors and is mainly expressed in reproductive tissues and muscles. Ligand binding to AR promotes its dissociation from heat shock proteins and other chaperones, leading to dimerization of the receptor, phosphorylation and subsequent translocation into the nucleus where AR binds to androgen responsive elements present in the regulatory regions of multiple genes involved in the growth, survival and differentiation of prostate cells.
The first non-steroidal anti-androgen, flutamide was approved for PCa in 1989 and the structurally related compounds, bicalutamide and nilutamide, were launched in 1995 and 1996, respectively. Non-steroidal compounds are more favorable than steroidal anti-androgens in clinical applications because of the lack of cross-reactivity with other steroid receptors and improved oral bioavailability. Of this structural class of propanamide anti-androgens, bicalutamide is the most potent, best tolerated and the leading anti-androgen on the market. Bicalutamide is described in patent literature for example in European patent EP 0100172. Certain arylamide derivatives have also been described in WO 2008/011072 A2 as selective androgen receptor modulators.
Unfortunately, although ADT and anti-androgen treatment typically result in early beneficial responses, PCa then progresses to a state where androgen deprivation fails to control the malignancy despite minimal testosterone levels. This state is termed castration-resistant prostate cancer (CRPC) (or hormone-refractory prostate cancer, HRPC) and is the lethal form of the disease. CRPC is believed to emerge after genetic and/or epigenetic changes in the prostate cancer cells and it is characterized by re-activation of the growth of cancer cells that have adapted to the hormone-deprived environment in the prostate.
The growth of cancer cells in CRPC remains dependent on the function of AR and studies over the past decade demonstrate that CRPC cells employ multiple mechanisms to re-activate AR. See Chen C D, Welsbie D S, Tran C. Baek S H, Chen R, Vessella R, Rosenfeld M G, Sawyers C L. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004 January; 10(1):33-39 and references therein. The major mechanisms include amplification of AR gene or up-regulation of AR mRNA or protein, point mutations in AR that allow activation of the AR by non-androgenic ligands or even anti-androgens, changes in the expression levels of co-activators and co-repressors of AR transcription, and expression of alternatively spliced and constitutively active variants of the AR. Thus, drugs targeting AR signaling could still be effective in the prevention and treatment of CRPC.
The limited utility of currently available anti-androgens is most likely related to an incomplete AR inhibition under certain circumstances (Taplin M E. Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nat Olin Pract Oncol, 2007 April; 4(4):236-244). Multiple molecular mechanisms may contribute to the failure of standard anti-androgen treatments. The use of anti-androgens that target ligand-binding domain of the AR, such as bicalutamide, can lead to selection of prostate cancer cells that harbor point mutations in the ligand-binding domain. In some cases these mutations can cause prostate cancer cells to convert antagonists to agonists. AR mutations are found in 10-40% of metastatic tumors. More than 70 mutations in the AR have been discovered, which result in increased basal activity of the receptor or widened ligand specificity.
For example, threonine to alanine mutation in amino acid 877 is the most frequently found mutation in PCa patients and converts flutamide, cyprotenone (steroidal anti-androgen), progesterone and estrogens agonistic in AR. Mutation in amino acid 741 from tryptophan to either leucine or cysteine accounts for the switch of bicalutamide from anti-androgen to an agonist (Hara T, Miyazaki J, Araki H, Yamaoka M, Kanzaki N, Kusaka M, Miyamoto M. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003 Jan. 1; 63(1):149-153.)
In addition to point mutations in AR, increased receptor levels can cause anti-androgens to function as agonists (Chen C D, Welsbie D S, Tran C, Baek S H, Chen R, Vessella R, Rosenfeld M G, Sawyers C L. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004 January;10(1):33-39). The antagonist-agonist conversion has significant clinical relevance. Approximately 30% of men with progressing PCa experience a paradoxical drop in serum prostate specific antigen levels after discontinuation of the anti-androgen treatment.
To date, treatment for CRPC has been disappointing with expected survival estimated at 7-16 months and no significant improvement with currently available therapies. Effective, novel agents that target AR are therefore needed.
More specifically, there is a need for new anti-androgen compounds that are more potent than bicalutamide in antagonizing the activities of endogenous androgens on AR. There is also a need for new anti-androgen compounds that exhibit minimal agonism in AR. Importantly, there is a need for novel anti-androgens that do not gain agonistic activity in CRPC related mutant ARs or in CRPC related settings in which AR is present at high amounts. In addition, there is a need for non-steroidal, non-toxic molecules with drug-like properties that can be used in the treatment and prevention of BPH, PCa and CRPC.
Now it has been surprisingly found that the arylamide derivatives according to the present invention overcome the disadvantages related to bicalutamide.